Long-term follow-up of pediatric sickle cell disease patients with abnormal high velocities on transcranial Doppler

Abstract Background: Hydroxyurea (HU) therapy reduces considerably mortality and morbility in sickle cell disease (SCD). In about 10–25% of adult patients HU is ineffective therefore other therapeutic options such as chronic red cell transfusions (CRT) or erythroexchange (EEX) are needed. From 1981 to 2007 in our Center 40 patients affected by homozygous sickle cell (S-S) and sickle-β0 thalassemia (S/β0) with a previous history of major events, pregnancy or prior to surgery were treated with periodic Manual Erithroexchange (MEEX). 1133 MEEX procedures were performed with only one case of immunization in a pregnant woman. Consequentely MEEX resulted to be safe and efficacious in preventing SCD manifestations as well as significantly inexpensive. Even if, since 1995 HU has been accepted as first line therapy, seven out of 40 patients, unresponsive to HU treatment, had been continuing on a program of periodic EEX. On the basis of our own experience, we decided to use manual EEX instead of automatic one. We retrospectively report the data referring to a long-term follow-up (11–26 yrs, medium 16,5 yrs) of these 7 patients. Methods and Patients: MEEX always started with an infusion of a 500 ml Ringer lactate solution followed by a phlebotomy (400–600 ml depending on weight and HbS level); autologous plasma derived from drawn blood centrifugation was re-infused to the patient. Thereafter a second phlebotomy was performed as previously described. Finally, depending on Hb level, each patient received two or three packed, Rh matched, leuko-filtered and plasma-depleted red cells units. A single peripheral venous access was required. The gap between each MEEX ranged from 45 to 90 days in order to maintain HbS levels below 60%. The seven patients (3 males and 4 females) affected by S/beta° (6 pts) and S-S (1pts), at the beginning of the MEEX program were aged 8 to 26 years (mean 14yrs). They were enrolled because of acute chest syndrome (2 pts) and >3 painful crises/yr (5pts). Patients underwent a median of 109 (61–180) MEEX procedures. Results: In the seven observed patients no adverse events related to the procedure (i.e. alloimmunization) was reported. During the follow-up neither typical acute complications of SCD, such as acute chest syndrome, splenic sequestration, stroke, bone necrosis, priapism, nor long term complications like renal failure, cerebrovascular or retinic damage, pseudoxanthoma like manifestations were observed. None of the typical iron overload consequences (hypogonadism, growth failure, hypotiroidism and diabetes) were noted. Concerning cardiac function, all subjects showed a left ventricular ejection fraction > 60% with no evidence of pulmonary hypertension, evaluated by echocardiography. LIC, assessed by SQUID or liver biopsy, was normal in all patients except one. This patient developed iron overload, requiring steady iron chelation therapy, due to CRT before entering the MEEX program at the age of 26 yrs. Cardiac T2* measured by MRI resulted >22mms in each patient. During the observation period 5 hospitalizations (4 acute cholecystitis and 1 Venous Occlusive Crisis) occurred. Only one patient needed chronic analgesic therapy to relieve head femur necrosis pain developed before starting periodic MEEXes. According to age all patients attended school or had a regular job. Discussion: The long-term follow-up revealed the above described procedure to be safe and efficacious in preventing acute and chronic complications of SCD in patients unresponsive to HU therapy, allowing them to have a good quality of life. This approach is less invasive and significantly less expensive than both CTR-chelation and automated EEX. Furthermore since MEEX is feasible and easy to manage it should be considered a treatment option also in developing countries, according to ASH SDC Policy Statements.

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Barriers to Pediatric Sickle Cell Disease Guideline Recommendations

Global Pediatric Health ◽

10.1177/2333794x19847026 ◽

2019 ◽

Vol 6 ◽

pp. 2333794X1984702 ◽

Cited By ~ 3

Author(s):

Michael D. Cabana ◽

Julie Kanter ◽

Anne M. Marsh ◽

Marsha J. Treadwell ◽

Michael Rowland ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Support Staff ◽

Cell Disease ◽

National Guidelines ◽

Convenience Sample ◽

Different Types ◽

Pediatric Sickle Cell Disease

National guidelines recommend that providers counsel all patients with sickle cell anemia about hydroxyurea (HU) therapy and screen children with sickle cell anemia annually for the risk of stroke with transcranial Doppler (TCD). We surveyed a national convenience sample of sickle cell disease clinicians to assess factors associated with low adherence. Adherence was 46% for TCD screening. Low adherence was associated with a lack of outcome expectancy (eg, a belief that there would be poor patient follow-up to TCD testing; P < .05). Adherence was 72% for HU counseling. Practice barriers (eg, lack of support staff or time) and a lack of agreement with HU recommendations were associated with low adherence ( P < .05). This study demonstrates that different types of strategies are needed to improve TCD screening (to address follow-up and access to testing) versus HU counseling (to address physician agreement and practice barriers).

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Five years of experience with hydroxyurea in children and young adults with sickle cell disease

Blood ◽

10.1182/blood.v97.11.3628 ◽

2001 ◽

Vol 97 (11) ◽

pp. 3628-3632 ◽

Cited By ~ 132

Author(s):

Alina Ferster ◽

Parvine Tahriri ◽

Christiane Vermylen ◽

Geneviève Sturbois ◽

Francis Corazza ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Laboratory Data ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Significant Difference ◽

History Of ◽

Ischemic Attack

The short-term beneficial effect of hydroxyurea (HU) in sickle cell disease (SCD) has been proven by randomized studies in children and adults. The Belgian registry of HU-treated SCD patients was created to evaluate its long-term efficacy and toxicity. The median follow-up of the 93 patients registered is 3.5 years; clinical and laboratory data have been obtained for 82 patients at 1 year, 61 at 2 years, 44 at 3 years, 33 at 4 years, and 22 after 5 years. On HU, the number of hospitalizations and days hospitalized dropped significantly. Analysis of the 22 patients with a minimum of 5 years of follow-up confirm a significant difference in the number of hospitalizations (P = .0002) and days in the hospital (P < .01), throughout the treatment when compared to prior to HU therapy. The probabilities of not experiencing any event or any vaso-occlusive crisis requiring hospitalization during the 5 years of treatment were, respectively, 47% and 55%. On HU, the rate per 100 patient-years of severe events was estimated to be 3.5% for acute chest syndrome, 1.2% for aplastic crisis, 0.4% for splenic sequestration; it was 0% for the 9 patients with a history of stroke or transient ischemic attack followed for an average of 4 years. No important adverse effect occurred. Long-term chronic treatment with HU for patients with SCD appears feasible, effective, and devoid of any major toxicity; in patients with a history of stroke, HU may be a valid alternative to chronic transfusion support.

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Sickle-Cell Disease Patients' Attitudes Towards Their Treatment with Hydroxycarbamide

Blood ◽

10.1182/blood-2019-125673 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1013-1013

Author(s):

Frédéric Galactéros ◽

Ersi Voskaridou ◽

Anoosha Habibi ◽

Giovanna Cannas ◽

Laure Joseph ◽

...

Keyword(s):

Sickle Cell Disease ◽

Board Of Directors ◽

Sickle Cell ◽

Research Funding ◽

Fetal Hemoglobin ◽

Treatment Discontinuation ◽

Cell Disease ◽

Advisory Committees

Hydroxyurea (HU) is approved in the EU and USA for prevention of vaso-occlusive crises (VOC) including acute chest syndromes (ACS) in patients over 2 years with sickle-cell disease (SCD). The major benefits of HU in SCD are directly related to its abilities to increase HbF, decrease sickling of red blood cells and hemolysis, leading to reduction of vaso-occlusive episodes, need for blood transfusions and consequently reduction of morbidity and mortality. Adherence to the treatment is paramount for effectiveness, but in spite of proven benefits, barriers to adherence persist.[1] ESCORT-HU study (European Sickle Cell Disease COhoRT - HydroxyUrea), is a multicentric, prospective, non-interventional European study designed to evaluate the safety profile of HU in real life. Patients were enrolled from January 2009 to June 2017 with a follow-up of up to 10 years. All interruptions and resumptions of HU treatment exceeding 15 days were recorded in this study. We hereby present the analysis of the group of patients who self-discontinued HU at least once during the study before informing their caregiver, with a view to identify potential barriers to long-term adherence. In total, 1906 patients were enrolled in ESCORT-HU from 63 centers in France, Germany, Greece and Italy. Of these, 619 patients (32%) stopped HU for over 15 days at least once, and around a third (11% of all patients) were due to patient's will. The mean duration of HU treatment before the first discontinuation was 4.8 ± 5.1 years. Data are summarized in table 1. Compared to the rest of the cohort, the 'treatment discontinuation' group had similar distribution by gender and indication for HU prescription, but a higher proportion of adults stopped HU more than 15 days. It is notable that the proportion of patients with SC genotype was higher in the 'treatment discontinuation' group (4.5% vs 1.7%). The patients in the 'treatment discontinuation' group had more frequent SCD symptoms before enrolment in the study (table 2). Hematological and clinical improvement compared to the baseline was observed in both groups. However, average mean Corpuscular Volume (MCV) and Fetal Hemoglobin percentage (HbF%) were lower and mean percentages of patients with SCD symptoms were higher over the three years of follow-up in the 'treatment discontinuation' group, suggesting that HU daily dose was insufficient (table 2). Sixty patients have no treatment resumption date reported which suggest a permanent interruption of their treatment. Among them 32% preferred to switch to another HU medicinal product and 13% have safety issue (table 3). Understanding and managing self-discontinuation of HU before taking medical advice is challenging for the physician. It is tempting to speculate that it may be due, at least in part, to lack of effectiveness potentially due to an underdosage of the treatment. Resistance to the treatment may also be suggested based on past literature data revealing a great variability in the response (determined by HbF%) to HU therapy. There is evidence that genetic modifiers affect individual response to HU.[2],[3] Finally, weariness from long-term use may also explain the patient's wish to discontinue HU. But treatment at optimal effective should be the primary goal of caregivers. [1]Smaldone A., Manwani D., Green NS, Greater number of perceived barriers to hydroxyurea associated with poorer health-related quality of life in youth with sickle cell disease, Pediatr Blood Cancer. 2019 [2] Steinberg MH, Voskaridou E, Kutlar A, Loukopoulos D, Koshy M, et al. (2003). Concordant fetal hemoglobin response to hydroxyurea in siblings with sickle cell disease. Am J Hematol 72: 121-126 [3] Ware RE, Despotovic JM, Mortier NA, Flanagan JM, He J, et al. (2011) Pharmacokinetics, pharmacodynamics, and pharmacogenetics of hydroxyurea treatment for children with sickle cell anemia. Blood 118: 4985-4991 Disclosures Galactéros: Addmedica: Membership on an entity's Board of Directors or advisory committees. Voskaridou:Celgene Corporation: Consultancy, Research Funding; Protagonist: Research Funding; Genesis: Consultancy, Research Funding; Acceleron: Consultancy, Research Funding; Addmedica: Membership on an entity's Board of Directors or advisory committees. Cannas:Addmedica: Membership on an entity's Board of Directors or advisory committees.

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Transcranial Doppler Screening Program Is Effective in Preventing Stroke in Children with Sickle Cell Disease

Blood ◽

10.1182/blood.v112.11.714.714 ◽

2008 ◽

Vol 112 (11) ◽

pp. 714-714 ◽

Cited By ~ 1

Author(s):

Henrietta Enninful-Eghan ◽

Renee H Moore ◽

Rebecca Ichord ◽

Janet L Kwiatkowski

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Transcranial Doppler ◽

Screening Program ◽

Treatment Protocol ◽

Cell Disease ◽

Transfusion Therapy ◽

Neurological Event ◽

The Impact

Abstract In the Cooperative Study of Sickle Cell Disease the incidence of stroke in SCD-SS was estimated to be 0.61 per 100 patient-years. Since that study, the use of transcranial Doppler ultrasonography (TCD) has become routine to detect children at high risk of stroke and regular transfusions have been shown to reduce the risk of stroke by over 95% in those with abnormal TCD studies. The impact of TCD screening on the overall incidence of stroke in children with SCD has not been studied extensively. We sought to determine the impact of our TCD screening and treatment protocol on the incidence of first stroke in a cohort of children followed at our Sickle Cell Center. Routine TCD screening was instituted at our Center in Oct, 1998. Our protocol includes annual TCD studies for children with normal TCD results (<170 cm/s), repeat study every 3 to 6 months in those with conditional results (170–199 cm/s), and within 1–4 weeks for children with abnormal results (≥200 cm/s). Chronic transfusion therapy is recommended for patients with confirmed abnormal TCD velocities. In the current study, the rate of stroke in the 8-y period prior to TCD screening (Sept 1, 1990-Aug 31, 1998 – Pre-TCD) was compared to the rate in the 8-y period after TCD screening began (Sept 1, 1998 – Aug 31, 2006 – Post TCD). Eligible subjects were patients less than 22 years old with a diagnosis of SCD-SS or SCD-Sβ0-thalassemia. Subjects with a history of stroke prior to Sept, 1990 or before enrollment in our Center were excluded. Cases of stroke or other neurological event were identified from our clinical database. The study neurologist reviewed all clinical data and radiological studies for each neurological event and classified events into one of the following categories: overt stroke - ischemic (neurological deficit conforming to a vascular territory with neuroimaging studies corresponding to the clinical deficit) or hemorrhagic not overt stroke (other neurological event), and indeterminate. Incidence rates for stroke were calculated and compared between the Pre and Post TCD groups using a test of binomial proportions. Subjects were followed until they had a stroke or neurological event, turned 22 years old, the end of the 8-y period or until the last clinic date. The pre-TCD group included 475 children with a total follow-up time of 3,137 person-years. Twenty-one patients had overt stroke, 3 had other neurologic events (1-seizure, 1-transient ischemic attack/syncope, 1-behavioral changes) and 2 were indeterminate. The post-TCD group included 530 children with 3,578 person-years follow-up. Two patients had overt stroke, 6 had other neurological events [1-diffuse encephalopathy with viral syndrome, 1-febrile seizure, 3-dizzy and/or syncope (one with hgb=2.7), 1-headache with <30 min arm/leg weakness – all with acute punctate infarcts whose location did not correspond to clinical presentation], and 1 was indeterminate. The incidence of overt stroke in the pre-TCD period was 0.67 per 100 person-years, compared with an incidence of 0.06 per 100 person-years in the post-TCD period (p < 0.001). The first stroke case in the post-TCD period was a 3.4 year-old with ACA velocities > 200 cm/s but no abnormal velocities in the ICA/MCA and the second occurred in a 1.2 year-old, prior to the age that screening is started. Thus, our TCD screening and treatment program has been successful in reducing the rate of first overt stroke, although small vessel ischemia, particularly in the setting of an additional insult such as severe anemia, may not be prevented. Further modifications such as the addition of ACA velocity to treatment criteria, earlier screening, or the addition of other neuroimaging studies might further reduce the risk of first stroke.

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A Phase 2 Clinical Study of HQK-1001 (2,2-dimethylbutyrate, sodium salt), a Fetal Hemoglobin Inducer, in Patients with Sickle Cell Disease

Blood ◽

10.1182/blood.v118.21.1066.1066 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1066-1066 ◽

Cited By ~ 1

Author(s):

Abdullah Kutlar ◽

Adlette Inati ◽

Ali T Taher ◽

Amal El-Beshlawy ◽

Marvin Reid ◽

...

Keyword(s):

Sickle Cell Disease ◽

Adverse Events ◽

Dose Level ◽

Sickle Cell ◽

Fetal Hemoglobin ◽

Controlled Study ◽

Phase 2 ◽

Cell Disease

Abstract Abstract 1066 Fetal hemoglobin (Hb F) induction (anti-switching therapy) is an effective therapeutic strategy in sickle cell disease (SCD), both for reducing acute complications such as painful episodes and acute chest syndrome, and decreasing hospitalizations and transfusion requirements. Long term use of the only approved anti-switching agent, hydroxyurea (HU) has also been shown to improve survival. Despite this, HU is still not widely prescribed, ∼30% of patients are non-responders, and there are concerns regarding long term use of this cytotoxic agent. There is, therefore, a clear need for alternative anti-switching agents with different mechanism(s) of action, that are not cytotoxic, and that could be used either alone, or in combination with HU to enhance Hb F response. HQK-1001, an orally bioavailable short-chain fatty acid, was shown to promote Hb F synthesis and prolong erythroid survival and proliferation in transgenic mice and non-human primate models. In a Phase 1/2, dose-escalation, placebo-controlled study in 24 patients with SCD, HQK-1001 given at 10, 20, and 30 mg/kg/day for 12 weeks was well tolerated, showed dose-proportional pharmacokinetics (PK), and resulted in dose-dependent increase in Hb F (A Kutlar et al, Blood 2010; 116: Abstract 943). This randomized open-label Phase 2 study is being conducted to evaluate the safety, PK, and effect on Hb F of HQK-1001 administered at a higher dose and for a longer duration than previously studied. Patients with SCD age 12 years and greater were randomized to receive HQK-1001 at 30 or 40 mg/kg daily for 26 weeks. Enrollment at the 50 mg/kg dose level was opened after the Safety Monitoring Committee conducted a planned interim safety data review of the first 12 patients treated for 4 weeks. HQK-1001 is administered as 900 mg tablets, and daily oral iron supplementation is given to patients with plasma ferritin levels less than 700 ng/mL. A minimum of 14 patients stratified 1-to-1 by HU use at baseline will be enrolled at each dose level. Between 25 April 2011 and 5 August 2011, 39 patients have been enrolled and received HQK-1001 at 30 mg/kg (n = 14), 40 mg/kg (n = 14), and 50 mg/kg (n = 11). Patients were enrolled in North America (n = 18), Lebanon (n = 15) and Egypt (n = 6). Median age was 22 years (range, 12–47) and 7 (18%) were less than 18 years old. There were 20 (51%) males and 19 (49%) females. Patients had either Hb-SS (n = 34) or Hb-Sβ0 (n = 5), and 25 (64%) were on HU at baseline and continued HU while on study. Four patients have discontinued HQK-1001 per protocol following a transfusion to treat a SCD complication. One patient discontinued HQK-1001 due to pancreatitis. This patient was found to have a stone in the common bile duct and subsequently died postoperatively from multiorgan failure. The most common adverse events considered by the investigator as possibly drug-related were nausea in 10 patients (26%), abdominal/epigastric pain, vomiting, and headache in 5 (13%) each, and somnolence and dizziness in 3 (8%) each. Drug-related adverse events were graded as mild or moderate except for 1 case each of pancreatitis and gastritis graded as severe. No myelosuppression was observed. Assessment of HQK-1001 effect on Hb F and hemoglobin (Hb) is limited due to short follow-up. In 19 patients in which baseline and Week 4 data are available, the mean value at baseline for Hb was 8.9 g/dL (range, 7.4–11.4) and for Hb F was 1.11 g/dL (range, 0.15–3.33). Eight patients had data available both for Weeks 4 and 8. On Week 8, total Hb increased from baseline by a mean of 0.3 g/dL (range, −0.7 to 1.2) and Hb F increased by a mean of 0.14 g/dL (range, −0.19 to 0.42). The figure reports individual changes in Hb F from baseline to Weeks 4 (dark bars) and Week 8 (light bars), with “X” denoting the 4 patients on HU, and shows an increase in Hb F in 7 of 8 patients for that period. Enrollment is expected to be completed in August 2011 and updated results will be available at the meeting. In conclusion, the safety profile of HQK-1001 is consistent with results reported in prior studies and shows no overlapping toxicity with HU. Hb F is apparently increased in 7 of 8 patients with data available at Week 8, and this increase is seen both in patients receiving HU or not. Longer follow-up is needed to fully assess the safety of HQK-1001 and the extent of its effect on Hb F, total Hb, and SCD-related events. Disclosures: Aiello: HemaQuest Pharmaceuticals: Employment. Johnson:HemaQuest Pharmaceuticals: Employment. White:HemaQuest Pharmaceuticals: Consultancy. Ghalie:HemaQuest Pharmaceuticals: Employment.

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Long-term treatment follow-up of children with sickle cell disease monitored with abnormal transcranial Doppler velocities

Blood ◽

10.1182/blood-2015-10-675231 ◽

2016 ◽

Vol 127 (14) ◽

pp. 1814-1822 ◽

Cited By ~ 46

Author(s):

Françoise Bernaudin ◽

Suzanne Verlhac ◽

Cécile Arnaud ◽

Annie Kamdem ◽

Isabelle Hau ◽

...

Keyword(s):

Sickle Cell Disease ◽

Transcranial Doppler ◽

Term Treatment ◽

Cell Disease ◽

Allogeneic Transplant ◽

Hydroxyurea Treatment ◽

Key Points ◽

Long Term Treatment

Key PointsChildren with normalized TCD on transfusions were safely switched to hydroxyurea treatment, but trimestrial Doppler follow-up is required. Allogeneic transplant allowed the safe stop of transfusions in all patients, even in those with abnormal velocities before transplant.

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Voxelotor: alteration of sickle cell disease pathophysiology by a first-in-class polymerization inhibitor

Therapeutic Advances in Hematology ◽

10.1177/20406207211001136 ◽

2021 ◽

Vol 12 ◽

pp. 204062072110011

Author(s):

Alexander K. Glaros ◽

Reza Razvi ◽

Nirmish Shah ◽

Ahmar U. Zaidi

Keyword(s):

Sickle Cell Disease ◽

Hemolytic Anemia ◽

Sickle Cell ◽

Clinical Stage ◽

Pharmaceutical Research ◽

Organ Damage ◽

Cell Disease ◽

Disease Modifying Drugs ◽

Long Term Follow Up

Sickle cell disease, despite its recognition as a severely debilitating genetic condition affecting hundreds of thousands of neonates throughout the world each year, was not a target of pharmaceutical research focus for most of its 100-year existence in the medical consciousness. This has changed in recent years as many novel therapeutics are currently under investigation, with three new disease-modifying drugs achieving FDA approval in the last 4 years. One of these drugs, voxelotor, is especially encouraging as an inhibitor of sickling for its ability to safely improve the chronic hemolytic anemia of sickle cell disease. This was demonstrated during all clinical phases of investigation by an average improvement in hemoglobin of greater than 1 g/dL, as well as statistically significant improvements in established markers of hemolysis. While anemia itself represents a potential cause of morbidity, it is more importantly a marker of the hemolysis known to cause the long-term vascular and organ damage that makes sickle cell disease so debilitating and frequently fatal early in life. Given the recency of the approval, there has not been sufficient long-term follow-up to demonstrate improvement in the chronic sequelae of sickle cell disease as a result of voxelotor-induced improvements in hemolytic anemia. There is hope, however, based on the experience with hydroxyurea improving morbidity and mortality via reductions in sickling and improved rheology, that voxelotor may have similar long-term benefits by positively manipulating the kinetics of hemoglobin polymerization. This review aims to summarize the targeted pathobiology of sickle cell disease, the mechanism of action of voxelotor, and the safety and efficacy data from preclinical to late clinical stage investigations of this long-awaited medication, in the hopes of better informing the decision-making process behind prescribing or not prescribing it for patients in need of intervention.

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